Compositions and methods for treating beta-amyloid related diseases   

This application is a continuation of International Patent Application Serial No. PCT/US2010/044683, filed Aug. 6, 2010, which claims the benefit of priority under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. (“USSN”) 61/293,783, filed Jan. 11, 2010; U.S. Ser. No. 61/232,383, filed Aug. 7, 2009; and U.S. Ser. No. 61/232,388, filed Aug. 7, 2009. Each of the aforementioned applications are expressly incorporated herein by reference in their entirety and for all purposes.

This invention was made with government support under grant number 4R44AG032784 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.

The invention generally relates to medicinal chemistry, veterinary medicine and cell biology. In alternative embodiments the invention provides compositions and methods for ameliorating diseases and conditions having a beta-amyloid component, including Alzheimer\'s disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cognitive Dysfunction Syndrome (CDS) and loss of cognition, in humans and in non-human animals. In alternative embodiments the invention provides analogs of AB-007 (E64d, or loxistatin) and its acid form E64c (loxistatin acid), their preparation, and pharmaceutical compositions thereof and methods of making and using same. In alternative embodiments compositions of the invention are deuterated analogs of AB-007 (or E64d or loxistatin) and E64c (or loxistatin acid). In alternative embodiments compositions of the invention are metabolically blocked forms as compared to AB-007 and loxistatin. In alternative embodiments compositions of the invention are used to ameliorate (including treat, slow, reverse or prevent) a disease or condition which can be ameliorated by partial or complete inhibition of a cysteine protease, e.g., Alzheimer\'s disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cognitive Dysfunction Syndrome (CDS) and loss of cognition in humans and in non-human animal. The invention also provides alternative dosage forms and formulations for AB-007 (E64d, loxistatin) and loxistatin acid (E64c), and for compounds of this invention.

AB-007 (also called loxistatin, E64d, EST or ((2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester) is an ethyl ester prodrug, 342.4 mol wt (MW), which is completely converted in vivo to its acid form E64c (also called loxistatin acid or Ep 475, 314.4 mol wt, which irreversibly inhibits proteases belonging to the cysteine protease class by covalently binding to sulfhydryl groups in the proteases\' active sites.

Two hydroxylated metabolites of loxistatin (or E64d) have been observed:

Reference: Fukushima, K. et al. “Metabolic fate of loxistatin in rat”, Xenobiotica, 1990, 20, 1043-1051. This metabolism, or in vivo hydroxylation, can result in lowering the effective concentration of the drug and shortens its half life in vivo.

Cathepsin B is co-localized with beta amyloid (Aβ) in plaques of AD brains and is elevated in cerebrospinal fluid (CSF) of Alzheimer Disease (AD) patients. Also, age-related changes in cathepsin B expression are consistent with the late age of onset of Alzheimer\'s. These findings, among others, indicate a role for cathepsin B in AD.

SUMMARY

In alternative embodiments the invention provides compositions and methods for treating, preventing, reversing, slowing the progression of and/or ameliorating diseases and conditions having a beta-amyloid (β-amyloid, or Aβ) component, including Alzheimer\'s disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cognitive Dysfunction Syndrome (CDS) and loss of cognition.

In alternative embodiments, the invention provides a compound of Formula I:

wherein

R is —H or alkyl;

each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from the group consisting of —H, -D, —F, —OH, and —CH3;

or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is not —H.

In alternative embodiments, the compounds have the stereochemistry of Formula I′:

In alternative embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from the group consisting of —H and -D. In alternative embodiments, each of R1, R2, R3, R4, and R5, is —H and each of R6, R7, R8, R9, and R10 is independently selected from the group consisting of —H and -D. In alternative embodiments, each of R1, R2, R3, R4, R5, and R10 is —H and each of R6, R7, R8, and R9 is independently selected from the group consisting of —H and -D. In alternative embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from the group consisting of —H and —F. In alternative embodiments, each of R1, R2, R3, R4, R5, and R10 is —H and each of R6, R7, R8, and R9 is independently selected from the group consisting of —H and —F. In alternative embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from the group consisting of —H and —OH. In alternative embodiments, each of R1, R2, R3, R4, R5, and R10 is —H and each of R6, R7, R8, and R9 is independently selected from the group consisting of —H and —OH. In alternative embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from the group consisting of —H and —CH3. In alternative embodiments, each of R1, R2, R3, R4, R5, and R10 is —H and each of R6, R7, R8, and R9 is independently selected from the group consisting of —H and —CH3.

In alternative embodiments, the invention provides a compound selected from the group consisting of:

or a pharmaceutically acceptable salts, hydrates, stereoisomers or solvates thereof.

In alternative embodiments, the invention provides a compound selected from the group consisting of:

or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof.

In alternative embodiments, the invention provides pharmaceutical compositions, dosage form or formulation comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof, with a pharmaceutically acceptable carrier or excipient,

and optionally the pharmaceutical composition, dosage form or formulation further comprises at least one other pharmaceutical composition, dosage form or formulation used to treat or ameliorate, or treat the symptoms of, or be palliative for, a cognitive dysfunction or a loss of cognition, a dementia or a pre-dementia, Alzheimer\'s disease (AD), Vascular Dementia (VD), and/or a Cognitive Dysfunction Syndrome (CDS) in humans or in a non-human animal, wherein optionally the at least one other pharmaceutical composition, dosage form or formulation comprises a selegiline (e.g., selegiline hydrochloride) or deprenyl, or ANIPRYL™; a donepezil (ARICEPT™); a carbamate; edrophonium or comparable reversible acetylcholinesterase inhibitor (e.g., TENSILON™, ENLON™, REVERSOL™); a neostigmine (e.g., PROSTIGMIN™, VAGOSTIGMIN™); a galantamine (e.g., NIVALIN™, RAZADYNE™, RAZADYNE ER™, REMINYL™); a rivastigmine (e.g., EXELON); a tarenflurbil or R-flurbiprofen (e.g., FLURIZAN™); and, any combination or equivalent thereof.

In alternative embodiments, of the pharmaceutical compositions, dosage forms or formulations, the composition is suitable for (or formulated for) topical, oral, parenteral, intrathecal or intravenous infusion administration, wherein optionally said composition is suitable for (or formulated for) administration as a (or in the form of a) patch, adhesive tape, gel, liquid or suspension, powder, spray, aerosol, lyophilate, lozenge, pill, geltab, tablet, capsule and/or implant. The pharmaceutical composition, dosage form or formulation can be suitable for (or formulated for) human or veterinary administration, wherein optionally said composition is suitable for (or formulated for) administration to a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat.

In alternative embodiments, the invention provides methods of inhibiting a cysteine protease, or a cathepsin, a caspase or a calpain, or a cathepsin L or a cathepsin B, or a cathepsin F, H, K, L1, L2, O, S, W, X or Z, in an individual, a tissue, an organ or a cell, comprising contacting said cell, tissue, organ or individual with a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I,

wherein optionally the contacting is in vitro, ex vivo or in vivo, and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat,

and optionally the tissue, organ or cell comprises a muscle cell, a nerve cell, muscle tissue, peripheral nervous system (PNS) and/or central nervous system (CNS) or brain,

and optionally by administering the compound or pharmaceutical composition, dosage form or formulation to the individual, a tissue, an organ or a cell a dementia or pre-dementia, a vascular dementia (VD) and/or an Alzheimer\'s disease (AD), is prevented, treated or ameliorated,

and optionally the compound or pharmaceutical composition, dosage form or formulation is administered to prevent, treat or ameliorate pre-clinical Alzheimer\'s, a mild cognitive impairment and/or Alzheimer\'s dementia or pre-dementia.

In alternative embodiments, the invention provides methods of inhibiting a cysteine protease, or a cathepsin, a caspase or a calpain, or a cathepsin L or a cathepsin B, or a cathepsin F, H, K, L1, L2, O, S, W, X or Z, in an individual or a patient, comprising administering to said individual or patient in need thereof an effective amount of a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I,

wherein optionally the administering is ex vivo or in vivo, and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat,

and optionally the compound or pharmaceutical composition, dosage form or formulation is targeted to, or directly administered to (or into) a tissue, organ or cell, wherein optionally the tissue, organ or cell comprises a muscle cell, a nerve cell, muscle tissue, peripheral nervous system (PNS) and/or central nervous system (CNS) or brain,

and optionally by administering the compound or pharmaceutical composition, dosage form or formulation the individual or patient is treated for (as a therapeutic or prophylactic treatment) a dementia or pre-dementia, a vascular dementia (VD) and/or an Alzheimer\'s disease (AD),

and optionally the compound or pharmaceutical composition, dosage form or formulation is administered to prevent, treat or ameliorate pre-clinical Alzheimer\'s, a mild cognitive impairment and/or Alzheimer\'s dementia or pre-dementia.

In alternative embodiments, the invention provides methods for preventing, slowing the progression of, treating or ameliorating a cognitive impairment, a dementia or pre-dementia, a vascular dementia (VD) or an Alzheimer\'s disease (AD), comprising administering to an individual or a patient, comprising administering to said individual or patient in need thereof an effective amount of a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I, wherein optionally the administering is ex vivo or in vivo, and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat), and optionally the compound or pharmaceutical composition, dosage form or formulation is administered to prevent, treat or ameliorate pre-clinical Alzheimer\'s, a mild cognitive impairment and/or Alzheimer\'s dementia or pre-dementia.

In alternative embodiments, the invention provides methods of reversing, slowing, reducing or preventing the effects of β-amyloid in an individual or patient comprising administering to the individual or patient in need thereof an effective amount of a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I, and optionally by reversing, slowing, reducing or preventing the effects of β-amyloid in the individual or patient, a dementia or pre-dementia, a vascular dementia (VD) and/or an Alzheimer\'s disease (AD), is treated or ameliorated, wherein optionally the administering is ex vivo or in vivo, and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat, and optionally the compound or pharmaceutical composition, dosage form or formulation is administered to prevent, treat or ameliorate pre-clinical Alzheimer\'s, a mild cognitive impairment and/or Alzheimer\'s dementia or pre-dementia.

In alternative embodiments, the invention provides methods of reversing, slowing, reducing or preventing neuronal cell death or apoptosis in a cell, an organ, a tissue, an individual or a patient comprising administering to the cell or tissue, or the individual or patient in need thereof, an effective amount of a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I, and optionally by reversing, slowing, reducing or preventing neuronal cell death or apoptosis in the cell, organ, tissue, individual or patient, a dementia or pre-dementia, a vascular dementia (VD) and/or an Alzheimer\'s disease (AD) is treated or ameliorated, wherein optionally the administering is ex vivo or in vivo, and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat, and optionally the compound or pharmaceutical composition, dosage form or formulation is administered to prevent, treat or ameliorate pre-clinical Alzheimer\'s, a mild cognitive impairment and/or Alzheimer\'s dementia or pre-dementia.

In alternative embodiments, the invention provides methods of slowing, reversing, reducing or preventing neuronal cell death in an individual, subject or patient comprising (a) administering to said individual, subject or patient an effective amount of a compound comprising:

(i) a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I; or

(ii) a loxistatin (also called E64d or AB-007) (also called (2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester), or loxistatin acid (also called E64c) conjugated to (or comprising) a chemical delivery system (CDS); or a composition as described in U.S. Patent Application Nos. 20080227806, 20080176841 and/or 20100048717;

such that neuronal cell death is slowed, reversed, reduced and/or prevented, wherein said effective amount is between about 1 mg and about 400 mg; or is between about 1 mg and about 250 mg; or is about 5 mg and about 150 mg; or is between about 1 mg and about 75 mg; or is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg;

(b) the method of (a), wherein the compound is formulated in a gel, spray, aerosol, powder, liquid or solid dosage form, or is formulated for administration as a (or in the form of a) patch, adhesive tape, gel, liquid or suspension, powder, spray, aerosol, lyophilate, lozenge, pill, geltab, tablet, capsule and/or implant;

(c) the method of (b), wherein the solid dosage form comprises an implant, a pill, a capsule, a geltab, a tablet or a lozenge; or

(d) the method of (a), (b) or (c), wherein the compound is administered as a once a day, or twice a day (bid), or three times a day (tid) formulation, optionally as an oral dosage,

and optionally the compound or pharmaceutical composition, dosage form or formulation is administered to prevent, treat or ameliorate a cognitive impairment, a dementia or pre-dementia, a vascular dementia (VD), an Alzheimer\'s disease (AD), or a pre-clinical Alzheimer\'s disease (AD), an Alzheimer\'s dementia or pre-dementia and/or a mild cognitive impairment;

and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat.

In alternative embodiments, the invention provides methods of slowing, reversing, reducing or preventing the effects or formation of β-amyloid, or β-amyloid accumulation, or β-amyloid plaque formation in an individual, subject or patient comprising

(a) administering to said individual, subject or patient an effective amount of a compound comprising:

(i) a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I; or

(ii) a loxistatin (also called E64d or AB-007) (also called (2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester), or loxistatin acid (also called E64c) conjugated to (or comprising) a chemical delivery system (CDS); or a composition as described in U.S. Patent Application Nos. 20080227806, 20080176841 and/or 20100048717;

such that the effects or formation of β-amyloid, or β-amyloid accumulation, or β-amyloid plaque formation is slowed, reversed, reduced and/or prevented, wherein said effective amount is between about 1 mg and about 400 mg; or is between about 1 mg and about 250 mg; or is about 5 mg and about 150 mg; or is between about 1 mg and about 75 mg; or is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg;

(b) the method of (a), wherein the compound is formulated in a gel, spray, aerosol, powder, liquid or solid dosage form, or is formulated for administration as a (or in the form of a) patch, adhesive tape, gel, liquid or suspension, powder, spray, aerosol, lyophilate, lozenge, pill, geltab, tablet, capsule and/or implant;

(c) the method of (b), wherein the solid dosage form comprises an implant, a pill, a capsule, a geltab, a tablet or a lozenge; or

(d) the method of (a), (b) or (c), wherein the compound is administered as a once a day, or a twice a day (bid), or a three times a day (tid) formulation, optionally as an oral dosage,

and optionally the compound or pharmaceutical composition, dosage form or formulation is administered to prevent, treat or ameliorate a cognitive impairment, a dementia or pre-dementia, a vascular dementia (VD), an Alzheimer\'s disease (AD) or a pre-clinical Alzheimer\'s disease (AD), a mild cognitive impairment and/or Alzheimer\'s dementia or pre-dementia, and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat.

In alternative embodiments, the invention provides methods of slowing, reversing, reducing or preventing a cognitive impairment, a dementia, an Alzheimer\'s Disease (AD), a vascular dementia (VD) and/or an Alzheimer\'s dementia or pre-dementia, in an individual, subject or patient comprising

(a) administering to said individual, subject or patient an effective amount of a compound comprising:

(i) a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I; or

(ii) a loxistatin (also called E64d or AB-007) (also called (2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester), or loxistatin acid (also called E64c) conjugated to (or comprising) a chemical delivery system (CDS); or a composition as described in U.S. Patent Application Nos. 20080227806, 20080176841 and/or 20100048717;

such that the cognitive impairment, AD, VD, dementia or pre-dementia, is slowed, reversed, reduced and/or prevented, wherein said effective amount is between about 1 mg and about 400 mg; or is between about 1 mg and about 250 mg; or is about 5 mg and about 150 mg; or is between about 1 mg and about 75 mg; or is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg;

(b) the method of (a), wherein the compound is formulated in a gel, spray, aerosol, powder, liquid or solid dosage form, or is formulated for administration as a (or in the form of a) patch, adhesive tape, gel, liquid or suspension, powder, spray, aerosol, lyophilate, lozenge, pill, geltab, tablet, capsule and/or implant;

(c) the method of (b), wherein the solid dosage form comprises an implant, a pill, a capsule, a geltab, a tablet or a lozenge; or

(d) the method of (a), (b) or (c), wherein the compound is administered as a once a day, or a twice a day (bid), or a three times a day (tid) formulation, optionally as an oral dosage,

and optionally the compound or pharmaceutical composition, dosage form or formulation is administered to prevent, treat or ameliorate a cognitive impairment, a dementia or pre-dementia, a vascular dementia (VD), Alzheimer\'s disease (AD), or a pre-clinical Alzheimer\'s, a mild cognitive impairment and/or Alzheimer\'s dementia or pre-dementia, and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat.

In alternative embodiments, the invention provides methods of slowing, reversing, reducing or preventing a Cognitive Dysfunction Syndrome (CDS) in a non-human animal, e.g., dogs and cats, including Canine or Cat (feline) Cognitive Dysfunction (CCD), comprising

(a) administering to said individual, subject or patient an effective amount of a compound comprising an inhibitor of a cysteine protease, or a cathepsin, a caspase or a calpain, or a cathepsin L or a cathepsin B, or a cathepsin F, H, K, L1, L2, O, S, W, X or Z, in an individual, a tissue, an organ or a cell,

wherein optionally the inhibitor comprises: (i) a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I; (ii) a loxistatin (also called E64d or AB-007) (also called (2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester), or loxistatin acid (also called E64c) conjugated to (or comprising) a chemical delivery system (CDS); or a composition as described in U.S. Patent Application Nos. 20080227806, 20080176841 and/or 20100048717; (iii) an odanacatib or MK-0674, or equivalents thereof; (iv) a diazomethyl ketone, a fluoromethyl ketone, an acyloxymethyl ketone, an O-acylhydroxylamine or a vinyl sulfone, or equivalents thereof; and/or (v) a reversible hydrazide inhibitor of cathepsin B comprising a ZLIII115A and ZLIII43A, or equivalents thereof; (vi) a cystatin, or a cystatin A, cystatin B, cystatin C (or cystatin 3) or cystatin D, or a type 1 cystatin (a stefin), a type 2 cystatin or a kininogen;

wherein optionally the Cognitive Dysfunction Syndrome (CDS) is slowed, reversed, reduced and/or prevented, wherein said effective amount is between about 1 mg and about 400 mg; or is between about 1 mg and about 250 mg; or is about 5 mg and about 150 mg; or is between about 1 mg and about 75 mg; or is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg;

(b) the method of (a), wherein the compound is formulated in a gel, spray, aerosol, powder, liquid or solid dosage form, or is formulated for administration as a (or in the form of a) patch, adhesive tape, gel, liquid or suspension, powder, spray, aerosol, lyophilate, lozenge, pill, geltab, tablet, capsule and/or implant;

(c) the method of (b), wherein the solid dosage form comprises an implant, a pill, a capsule, a geltab, a tablet or a lozenge; or

(d) the method of (a), (b) or (c), wherein the compound is administered as a once a day, or a twice a day (bid), or a three times a day (tid) formulation, optionally as an oral dosage,

and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat, and optionally CDS encompasses a Canine or Cat (feline) Cognitive Dysfunction (CCD).

In alternative embodiments, the invention provides products of manufacture, e.g., provides a blister pack or a plurality of blister packettes, a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, or a paper, plastic or cellophane package or a plurality of packettes, comprising:

(a) a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, and/or a compound of Formula I; and

(b) at least one other (e.g., at least one additional, different) compound, pharmaceutical composition, dosage form or formulation of (a), wherein the at least one other (e.g., at least one additional, different) compound, pharmaceutical composition, dosage form or formulation is used to treat or ameliorate, or treat the symptoms of, or be palliative for: a cognitive dysfunction or a loss of cognition, a dementia or a pre-dementia, Alzheimer\'s disease (AD), Vascular Dementia (VD), and/or a Cognitive Dysfunction Syndrome (CDS), in humans or in a non-human animal,

wherein optionally the at least one other pharmaceutical composition, dosage form or formulation comprises a selegiline (e.g., selegiline hydrochloride) or deprenyl, or ANIPRYL™; a donepezil (ARICEPT™); a carbamate; edrophonium or comparable reversible acetylcholinesterase inhibitor (e.g., TENSILON™, ENLON™, REVERSOL™); a neostigmine (e.g., PROSTIGMIN™, VAGOSTIGMIN™); a galantamine (e.g., NIVALIN™, RAZADYNE™, RAZADYNE ER™, REMINYL™); a rivastigmine (e.g., EXELON); a tarenflurbil or R-flurbiprofen (e.g., FLURIZAN™); and, any combination or equivalent thereof, or a nutritional supplement or a vitamin, e.g., vitamin E, vitamin B12 or a folic acid supplement, or any equivalent or combination thereof, or a pain treatment or pain palliative or an anti-inflammatory drug, e.g., an ibuprofen (e.g., ADVIL™, MOTRIN™), naproxen sodium (ALEVE™), indomethacin (INDOCIN™), or any equivalent or combination thereof, or a non-steroidal anti-inflammatory drug (a NSAID), e.g., a cyclooxygenase (COX) (or prostaglandin synthase) inhibitor, e.g., an etodolac (e.g., LODINE™, LODINE SR™ or ECCOXOLAC™), naproxen, celecoxib, rofecoxib, etoricoxib, valdecoxib, parecoxib, nabumetone, diclofenac, lumiracoxib, or equivalent, or a neuropathic pain analgesic such as gabapentin or pregabalin.

In alternative embodiments, the invention provides methods for lowering body or blood homocysteine or cystathionine in an individual, subject or patient, comprising

(a) administering to said individual, subject or patient an effective amount of a compound comprising an inhibitor of a cysteine protease, or a cathepsin, a caspase or a calpain, or a cathepsin L or a cathepsin B, or a cathepsin F, H, K, L1, L2, O, S, W, X or Z, in an individual, a tissue, an organ or a cell,

wherein optionally the inhibitor comprises: (i) a compound of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I; (ii) a loxistatin (also called E64d or AB-007) (also called (2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester), or loxistatin acid (also called E64c) conjugated to (or comprising) a chemical delivery system (CDS); or a composition as described in U.S. Patent Application Nos. 20080227806, 20080176841 and/or 20100048717; (iii) an odanacatib or MK-0674, or equivalents thereof; (iv) a diazomethyl ketone, a fluoromethyl ketone, an acyloxymethyl ketone, an O-acylhydroxylamine or a vinyl sulfone, or equivalents thereof; and/or (v) a reversible hydrazide inhibitor of cathepsin B comprising a ZLIII115A and ZLIII43A, or equivalents thereof; (vi) a cystatin, or a cystatin A, cystatin B, cystatin C (or cystatin 3) or cystatin D, or a type 1 cystatin (a stefin), a type 2 cystatin or a kininogen;

wherein optionally said effective amount is between about 1 mg and about 400 mg; or is between about 1 mg and about 250 mg; or is about 5 mg and about 150 mg; or is between about 1 mg and about 75 mg; or is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg;

(b) the method of (a), wherein the compound is formulated in a gel, spray, aerosol, powder, liquid or solid dosage form, or is formulated for administration as a (or in the form of a) patch, adhesive tape, gel, liquid or suspension, powder, spray, aerosol, lyophilate, lozenge, pill, geltab, tablet, capsule and/or implant;

(c) the method of (b), wherein the solid dosage form comprises an implant, a pill, a capsule, a geltab, a tablet or a lozenge; or

(d) the method of (a), (b) or (c), wherein the compound is administered as a once a day, or a twice a day (bid), or a three times a day (tid) formulation, optionally as an oral dosage;

and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat;

and optionally the compound is administered to lower homocysteine levels to below 10 micromoles/liter.

In alternative embodiments, the invention provides methods for lowering or decreasing the risk of heart attacks, strokes, blood clot formation in an individual, subject or patient, comprising

(a) administering to an individual, subject or patient an effective amount of a compound comprising an inhibitor of a cysteine protease, or a cathepsin, a caspase or a calpain, or a cathepsin L or a cathepsin B, or a cathepsin F, H, K, L1, L2, O, S, W, X or Z, in an individual, a tissue, an organ or a cell,

wherein optionally the inhibitor comprises: (i) a compound of any of the invention, or a pharmaceutical composition, dosage form or formulation of the invention, or a compound of Formula I; (ii) a loxistatin (also called E64d or AB-007) (also called (2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester), or loxistatin acid (also called E64c) conjugated to (or comprising) a chemical delivery system (CDS); or a composition as described in U.S. Patent Application Nos. 20080227806, 20080176841 and/or 20100048717; (iii) an odanacatib or MK-0674, or equivalents thereof; (iv) a diazomethyl ketone, a fluoromethyl ketone, an acyloxymethyl ketone, an O-acylhydroxylamine or a vinyl sulfone, or equivalents thereof; and/or (v) a reversible hydrazide inhibitor of cathepsin B comprising a ZLIII115A and ZLIII43A, or equivalents thereof; (vi) a cystatin, or a cystatin A, cystatin B, cystatin C (or cystatin 3) or cystatin D, or a type 1 cystatin (a stefin), a type 2 cystatin or a kininogen;

wherein optionally said effective amount is between about 1 mg and about 400 mg; or is between about 1 mg and about 250 mg; or is about 5 mg and about 150 mg; or is between about 1 mg and about 75 mg; or is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg;

(b) the method of (a), wherein the compound is formulated in a gel, spray, aerosol, powder, liquid or solid dosage form, or is formulated for administration as a (or in the form of a) patch, adhesive tape, gel, liquid or suspension, powder, spray, aerosol, lyophilate, lozenge, pill, geltab, tablet, capsule and/or implant;

(c) the method of (b), wherein the solid dosage form comprises an implant, a pill, a capsule, a geltab, a tablet or a lozenge; or

(d) the method of (a), (b) or (c), wherein the compound is administered as a once a day, or a twice a day (bid), or a three times a day (tid) formulation, optionally as an oral dosage;

and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat;

and optionally the compound is administered to lower homocysteine levels to below 10 micromoles/liter.

In alternative embodiments, the invention provides methods for treating, preventing, slowing the progression of, reversing or ameliorating traumatic central nervous system (CNS) (e.g., brain) injury (due to, e.g., trauma, infection, surgery, and the like) and related (e.g., as sequelae or side effects) post-traumatic injuries, including traumatic war neurosis, post traumatic stress disorder (PTSD) or post-traumatic stress syndrome (PTSS), and cognitive, learning or memory impairments resulting therefrom, in an individual, subject or patient, comprising:

(a) administering to an individual, subject or patient an effective amount of a compound comprising an inhibitor of a cysteine protease, or a cathepsin, a caspase or a calpain, or a cathepsin L or a cathepsin B, or a cathepsin F, H, K, L1, L2, O, S, W, X or Z, in an individual, a tissue, an organ or a cell,

wherein optionally the inhibitor comprises: (i) a compound of the invention, or a pharmaceutical composition, a dosage form or a formulation of the invention, or a compound of Formula I; (ii) a loxistatin (also called E64d or AB-007) (also called (2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester), or loxistatin acid (also called E64c) conjugated to (or comprising) a chemical delivery system (CDS); or a composition as described in U.S. Patent Application Nos. 20080227806, 20080176841 and/or 20100048717; (iii) an odanacatib or MK-0674, or equivalents thereof; (iv) a diazomethyl ketone, a fluoromethyl ketone, an acyloxymethyl ketone, an O-acylhydroxylamine or a vinyl sulfone, or equivalents thereof; and/or (v) a reversible hydrazide inhibitor of cathepsin B comprising a ZLIII115A and ZLIII43A, or equivalents thereof; (vi) a cystatin, or a cystatin A, cystatin B, cystatin C (or cystatin 3) or cystatin D, or a type 1 cystatin (a stefin), a type 2 cystatin or a kininogen;

wherein optionally said effective amount is between about 1 mg and about 400 mg; or is between about 1 mg and about 250 mg; or is about 5 mg and about 150 mg; or is between about 1 mg and about 75 mg; or is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg;

(b) the method of (a), wherein the compound is formulated in a gel, spray, aerosol, powder, liquid or solid dosage form, or is formulated for administration as a (or in the form of a) patch, adhesive tape, gel, liquid or suspension, powder, spray, aerosol, lyophilate, lozenge, pill, geltab, tablet, capsule and/or implant;

(c) the method of (b), wherein the solid dosage form comprises an implant, a pill, a capsule, a geltab, a tablet or a lozenge; or

(d) the method of (a), (b) or (c), wherein the compound is administered as a once a day, or a twice a day (bid), or a three times a day (tid) formulation, optionally as an oral dosage;

and optionally the individual is a human or a non-human animal, and optionally the individual or non-human animal is a domestic, zoo, laboratory or farm animal, and optionally the animal is a dog or a cat.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 graphically illustrates data showing the measurement of brain Aβ40 and Aβ42 for 10 mg/kg/day dosing after 7 days compared to vehicle treated controls, as discussed in detail in Example 8, below.

FIG. 2 graphically illustrates data showing the measurements of brain Aβ1-40 in guinea pigs administered between 0 and 50 mg/kg/day AB-007 via oral gavage for 7 days, as discussed in detail in Example 8, below.

FIG. 3 graphically illustrates data showing the measurements of brain Aβ1-42 in guinea pigs administered between 0 and 50 mg/kg/day AB-007 via oral gavage for 7 days, as discussed in detail in Example 8, below.

FIG. 4 graphically illustrates data showing the measurements of Cathepsin B activity after administration of between 0 and 50 mg/kg/day AB-007 to guinea pigs via oral gavage for 7 days, as discussed in detail in Example 8, below.

FIG. 5 graphically illustrates data showing the measurements of BACE-1 activity after administration of between 0 and 50 mg/kg/day AB-007 to guinea pigs via oral gavage for 7 days, as discussed in detail in Example 8, below.

FIG. 6 graphically illustrates data showing that once-a-day oral administration of AB-007 (E64d, loxistatin) to guinea pigs results in a dose response reduction in FIG. 6(A) brain Aβ(40), FIG. 6(B) brain Aβ(42), FIG. 6(C) CSF Aβ, FIG. 6(D) CSF Aβ(42), FIG. 6(E) plasma Aβ(40) and FIG. 6(F) plasma Aβ(42), as discussed in detail in Example 9, below.

FIG. 7A graphically illustrates data showing that once-a-day for one week oral administration of AB-007 (E64d, loxistatin) to guinea pigs results in a dose response reduction brain cathepsin B activity; FIG. 7(B) (lower graph) illustrates that the same treatment results in an increase in brain BACE1 activity, as discussed in detail in Example 9, below.

FIG. 8 graphically illustrates data showing paired guinea pig data for brain Aβ(40) or Aβ(42) versus (vs) brain cathepsin B or BACE1 activity, respectively for the combined AB-007 (E64d, loxistatin) dose groups: FIG. 8(A) Brain Aβ(40) vs brain cathepsin B activity shows a significant positive correlation, showing that brain cathepsin B inhibition reduces brain Aβ(40); FIG. 8(B) Brain Aβ(42) vs brain cathepsin B activity also has a significant positive correlation, showing brain cathepsin B inhibition reduces brain Aβ(42); FIG. 8(C): Brain Aβ(40) vs brain BACE1 activity demonstrates a small negative correlation; and, FIG. 8(D) Brain Aβ(42) vs brain BACE1 activity has a negative correlation, as discussed in detail in Example 9, below.

FIG. 9 graphically illustrates data showing paired guinea pig data for brain Aβ(40) vs Aβ(42) and brain cathepsin B vs BACE1 activity for all AB-007 (E64d, loxistatin) dose groups combined: FIG. 9(A) Brain Aβ(40) vs Aβ(42) shows a significant positive correlation; and, FIG. 9(B) Brain cathepsin B vs BACE1 activity shows a slight negative correlation, as discussed in detail in Example 9, below.

FIG. 10 graphically illustrates data showing that once-a-day for a week oral administration of the invention\'s exemplary composition of the invention, the hepta-deuterated “E64d7”, to guinea pigs results in a dose response reduction in FIG. 10(A) brain Aβ(40), FIG. 10(B) brain Aβ(42), FIG. 10(C) CSF Aβ, FIG. 10(D) CSF Aβ(42), FIG. 10(E) plasma Aβ(40) and FIG. 10(F) plasma Aβ(42), as discussed in detail in Example 9, below.

FIG. 11A (upper graph) graphically illustrates data showing that once-a-day oral administration of E64d7 to guinea pigs results in a dose response reduction of brain cathepsin B activity, which is similar to the biphasic lowering of Aβ; FIG. 11B (lower graph) graphically illustrates data showing that same treatment results in an increase in brain BACE1 activity, as discussed in detail in Example 9, below.

FIG. 12 graphically illustrates data showing paired guinea pig data for brain Aβ(40) or Aβ(42) vs brain cathepsin B or BACE1 activity, respectively for the combined “E64d7” dose groups: FIG. 12(A) Brain Aβ(40) vs brain cathepsin B activity shows a significant positive correlation; FIG. 12(B) Brain Aβ(42) vs brain cathepsin B activity also has a significant positive correlation; FIG. 12(C) Brain Aβ(40) vs brain BACE1 activity demonstrates a small negative correlation; FIG. 12(D) Brain Aβ(42) vs brain BACE1 activity has a negative correlation, as discussed in detail in Example 9, below.

FIG. 13 graphically illustrates data showing paired guinea pig data for brain Aβ(40) vs Aβ(42) and brain cathepsin B vs BACE1 activity for all “E64d7” dose groups combined: FIG. 13(A) (upper graph) Brain Aβ(40) vs Aβ(42) shows a significant positive correlation; FIG. 13(B) Brain cathepsin B vs BACE1 activity shows a slight negative correlation, as discussed in detail in Example 9, below.

FIG. 14 graphically illustrates data showing the brain Aβ(40) and Aβ(42) data from the AB-007 (E64d, loxistatin)-doped mouse chow experiments, results from two experimental groups are shown: FIG. 14(A) Feeding the E64d doped chow for 1 or 3 months caused a significant reduction in brain Aβ(40) in both the young and old mice relative to age-matched controls; FIG. 14(B) the E64d doped chow fed for 1 or 3 months also caused a significant reduction in brain Aβ(42) in both the young and old mice relative age-matched controls, as discussed in detail in Example 9, below.

FIG. 15 graphically compares the data shown in FIG. 14, for brain Aβ(40) and Aβ(42) levels in young and old animals feed E64d doped chow for 1 or 3 months: FIG. 15(A) The brain Aβ(40) data from 1 month feeding; FIG. 15(B) the brain Aβ(40) data from 3 month feeding; FIG. 15(C) the brain Aβ(42) data from 1 month feeding; FIG. 15(D) the brain Aβ(42) data from 3 month feeding are shown, as discussed in detail in Example 9, below.

FIG. 16 graphically illustrates data showing the effects of AB-007 (E64d, loxistatin)-doped chow on the spatial memory deficit that develops in transgenic APPlon mice, as discussed in detail in Example 9, below.

FIG. 17 graphically illustrates data showing a paired data analysis from the mouse experiments between brain Aβ(40) or Aβ(42) peptides and latency period for young and old mice either treated or not with AB-007 (E64d, loxistatin): FIG. 17(A) graphically illustrates the effect of feeding young mice either the control or E64d-doped chow for 1 month on brain Aβ(40) peptide and latency period is shown; FIG. 17(B) graphically illustrates the effect of the E64d-doped chow feeding on young animals on brain Aβ(42) peptide vs. latency period is shown; FIG. 17(C) graphically illustrates the effect of the E64d-doped chow feeding on old animals on brain Aβ(40) peptide and latency period is shown; FIG. 17(D) graphically illustrates the effect of the E64d-doped chow feeding on old animals on brain Aβ(42) and latency period is shown; as discussed in detail in Example 9, below.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

In alternative embodiments the invention provides compositions and methods for preventing, treating, slowing the progress of, reversing or ameliorating diseases and conditions having a beta-amyloid component, including cognitive dysfunctions and loss of cognition, dementias and pre-dementias, Alzheimer\'s disease (AD), Vascular Dementia (VD), and Cognitive Dysfunction Syndrome (CDS) in humans or in a non-human animal.

In alternative embodiments the invention provides analogs of AB-007 (also called loxistatin or E64d) and its acid form E64c (also called loxistatin acid), their preparation, and pharmaceutical compositions thereof and methods of making and using same. In alternative embodiments, AB-007 (loxistatin) and/or E64c (loxistatin acid) are derivatized, e.g. deuterated, in one or more sites, e.g., a site relevant to a metabolic site, e.g., a site on the molecule involved and/or altered (e.g., hydroxylated) in its metabolism or breakdown in vivo. In alternative embodiments, the derivatization, e.g., a deuteration, results in altered metabolism, e.g., slowed or blocked metabolism, of a composition of the invention. Thus, in alternative embodiment compositions of the invention have “better” pharmacokinetic properties than the “parent” AB-007 (loxistatin, E64d) or E64c (loxistatin acid), e.g., because (noting the invention is not limited by any particular mechanism of action) the derivatization slows or inhibits the hydroxylation of AB-007 or E64c, a lower dosage is effective and/or more potent and an individual can be given a lower dosage to produce the same effect from a comparative dosage and/or formulation of the “parent” AB-007 or E64c.

In one embodiment, to block or slow the drug\'s (a composition of the invention) metabolism, e.g., hydroxylation, one or more hydrogen atoms extracted in the in vivo metabolic process and/or otherwise involved in the metabolic process is substituted by a moiety which is more difficult to (e.g., enzymatically) remove, e.g., deuterium. In alternative embodiments, one or more selected hydrogens are substituted (replaced) with a hydroxyl, deuterium, fluorine or a methyl group or a combination thereof.

For example, in alternative embodiments, compositions of the invention comprise a hepta-deuterated (or 7-position deuterated) AB-007 (loxistatin, E64d) and a hepta-deuterated (or 7-position deuterated) loxistatin acid (E64c):

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